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AMERICAN JOURNAL OF MEDICAL GENETICS PART A, 2025 (SCI-Expanded)
Maple syrup urine disease (MSUD) is a rare inborn error of metabolism caused by impaired catabolism of branched-chain amino acids (BCAAs). The genes BCKDHA, BCKDHB, DBT, and DLD encode the subunits of the branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex, which is essential for BCAA metabolism. Catalytic subunits are BCKDHA, BCKDHB, DBT, and DLD, whereas the regulator subunits are PPM1K and BCKDK. PPM1K plays a critical role by dephosphorylating and activating this enzyme complex. Pathogenic variants in the PPM1K gene cause an extremely rare, mild form of MSUD. Here, we report an 8-year-old male patient with a mild form of MSUD putatively caused by a novel homozygous variant in PPM1K. The patient presented with mild dysmorphic features, delayed speech, relative microcephaly, and overweight, all considered familial phenotypic traits. Laboratory findings revealed mildly elevated plasma branched-chain amino acids, mild lactic acidemia, and a slight increase in urinary keto acids. Exome sequencing identified a novel homozygous missense variant, c.925A>G p.(Ile309Val), in the PPM1K gene. This case represents the third reported patient with a mild form of MSUD associated with the first reported missense variant in the PPM1K gene in the literature, further expanding the clinical and genetic spectrum of PPM1K-related disorders.